JP7453284B2 - 癌のバイオマーカーとしてのpd-ecgf - Google Patents
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- JP7453284B2 JP7453284B2 JP2022113650A JP2022113650A JP7453284B2 JP 7453284 B2 JP7453284 B2 JP 7453284B2 JP 2022113650 A JP2022113650 A JP 2022113650A JP 2022113650 A JP2022113650 A JP 2022113650A JP 7453284 B2 JP7453284 B2 JP 7453284B2
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Description
(i)前記対象に由来するサンプル中のPD-ECGFのレベルを決定することと、
(ii)(i)で得られたレベルを基準値と比較することと、
を含み、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して増加している場合には、対象は癌と診断され、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して減少している場合には、対象は癌と診断されない、
方法に関する。
(i)前記対象に由来するサンプル中のPD-ECGFのレベルを決定することと、
(ii)(i)で得られたレベルを基準値と比較することと、
を含み、
前記抗血管新生療法はドキソルビシン療法またはインターフェロン療法ではなく、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して増加している場合、それは、抗血管新生療法に対する悪い応答を示しており、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して減少している場合、それは、抗血管新生療法に対する良好な応答を示している、
方法に関する。
本明細書で使用される場合、「抗血管新生療法(anti-angiogenic treatment)」または「抗血管新生療法(anti-angiogenesis treatment)」なる用語は、少なくとも1種の抗血管新生剤に基づく処置に関する。「抗血管新生剤(anti-angiogenic agent)」または「抗血管新生剤(anti-angiogenesis agent)」または「血管新生阻害剤」なる用語は、限定されるものではないが腫瘍血管新生を含む血管新生(例えば、血管を形成するプロセス)を標的とする作用物質に関する。これに関連して、阻害は、血管の形成を阻止すること、および血管の成長を停止または鈍化させること、を指し得る。
本発明の著者等は、組織サンプルを免疫組織化学によって分析したところ、非癌性組織サンプルではPD-ECGFの発現は検出されない(12のうち0、0%)が、69人のRCC患者のうち67(97%超)の組織サンプルで、および乳癌患者由来の組織サンプルでは16のうち9(56%)で、PD-ECGFタンパク質の発現が検出されるということを見出した(実施例1を参照のこと)。同様に、ELISAによって分析したところ、16人のRCC患者のうち14(87%超)の血漿サンプルで、乳癌患者由来の血漿サンプルでは16のうち11(69%)で、および結腸直腸癌患者由来の血漿サンプルでは58のうち52(90%)で、PD-ECGFの発現が観察された(実施例2を参照のこと)。
(i)前記対象に由来するサンプル中のPD-ECGFのレベルを決定することと、
(ii)(i)で得られたレベルを基準値と比較することと、
を含み、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して増加している場合には、対象は癌と診断され、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して減少している場合には、対象は癌と診断されない、
方法に関する。
本発明の著者等は、癌患者において決定されたPD-ECGFのレベルが、抗血管新生療法による処置の後に患者が早期進行を示すというリスクとの統計的に有意な相関を示すということを見出した。従って、さらなる態様では、本発明は、癌に罹患しており抗腫瘍処置を受けている対象において処置に対する応答を予測するための方法であって、
(i)前記対象に由来するサンプル中のPD-ECGFのレベルを決定することと、
(ii)(i)で得られたレベルを基準値と比較することと、
を含み、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して増加している場合、それは、処置に対する癌患者の不良な応答を示しており、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して減少している場合、それは、処置に対する癌患者の良好な応答を示している、
方法に関する。
(i)前記対象に由来するサンプル中のPD-ECGFのレベルを決定することと、
(ii)(i)で得られたレベルを基準値と比較することと、
を含み、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して増加している場合、それは、抗血管新生療法に対する悪い応答を示しており、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して減少している場合、それは、抗血管新生療法に対する良好な応答を示している、
方法に関する。
(i)前記対象に由来するサンプル中のPD-ECGFのレベルを決定することと、
(ii)(i)で得られたレベルを基準値と比較することと、
を含み、
前記抗血管新生療法はドキソルビシン療法またはインターフェロン療法ではなく、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して増加している場合、それは、抗血管新生療法に対する悪い応答を示しており、
対象に由来するサンプル中のPD-ECGFのレベルが基準値と比較して減少している場合、それは、抗血管新生療法に対する良好な応答を示している、
方法に関する。
別の態様では、本発明は、対象における癌の診断および/または抗血管新生療法に対する癌患者の応答の予測におけるPD-ECGFの使用に関する。より具体的には、本発明は、対象における癌の診断および/または抗血管新生療法に対する癌患者の応答の予測におけるPD-ECGFの使用であって、前記抗血管新生療法はドキソルビシン療法またはインターフェロン療法ではない、使用に関する。
・12の非癌性組織において、PD-ECGFは検出されなかった。従って、癌患者において非癌性組織のPD-ECGFのレベルと腫瘍塊のPD-ECGFのレベルとの間には有意な差がある(Mann-Whitney検定、p<0.0001)(図1)。
・免疫組織化学によって分析したところ、69人のRCC患者のうち67(97%超)の組織サンプルで、および乳癌患者由来の組織サンプルでは16のうち9(56%)で、PD-ECGFのタンパク質発現が観察された。
・PD-ECGFは種々の局在(膜、細胞質および核)を有し、これは、局在に応じた発現の種々の度合を評価することを可能にする。
・PD-ECGFは、各腫瘍の固有の特徴に依存した種々の発現レベルを示す。
・癌患者と比較して、健康な対象では血漿PD-ECGFレベルは検出できなかった。定量的には、健康な対象のPD-ECGFレベルと癌患者におけるPD-ECGFの血漿レベルとの間には統計的に有意な差がある(Mann-Whitney検定、p=0.0013)(図5)。
・ELISAによって分析したところ、16人のRCC患者のうち14(87%超)の血漿サンプルで、乳癌患者由来の血漿サンプルでは16のうち11(69%)で、および結腸直腸癌患者由来の血漿サンプルでは58のうち52(90%)で、PD-ECGFのタンパク質発現が観察された。
・PD-ECGFは、各患者の特徴に依存した種々の発現レベルを示す。
・PD-ECGFの基底発現レベルを分析したところ、患者は、おそらくは各患者の固有の特徴に依存して、種々の基底発現レベルを示す(図6、図7および図8)ということが観察された。
・63人の患者に由来するRCC組織サンプルにおいてPD-ECGFを評価した。RCC患者においてPD-ECGFの組織レベルの高さと早期進行のリスクの高さとの間には有意な関連性がある(Kaplan-Meier検定とGehan-Breslow-Wilcoxon検定、p=0.045)(図4)。
・52人の患者に由来する結腸直腸癌血漿サンプルにおいてPD-ECGFを評価した。結腸直腸癌患者においてPD-ECGFの血漿レベルと早期進行のリスクとの間には、疾患進行におけるPD-ECGFのレベルについての有意なハザード比によって表される有意な関連性がある(ハザード比の事後確率を用いてデータを評価し、ハザード比が1より高い事後確率は0.041に相当した。これは、腫瘍進行とPD-ECGFのレベルとの間の関連性を示す)(図9)。
・14人の患者に由来するRCC血漿サンプルにおいてPD-ECGFを評価した。RCC患者においてPD-ECGFの血漿レベルの高さと早期進行のリスクの高さとの間には有意な関連性がある(Kaplan-Meier検定とLog rank(Mantel-Cox)検定、p<0.07)(図10)。
PD-ECGFの発現レベルと癌の予後との間の関係を分析するために、本願の発明者等は、cBioPortal for Cancer Genomics(www.cbioportal.org)を使用することにより、PD-ECGFの低発現または高発現を伴う癌患者に基づいてKaplan-Meier生存曲線を生成した(図A-M)。
・PD-ECGFの変化を伴う結腸直腸腺癌の症例では、PD-ECGFの変化を伴わない症例よりも無病生存が悪い(図11);
・PD-ECGFの変化を伴う膠芽腫の症例では、PD-ECGFの変化を伴わない症例よりも全生存が悪い(図12);
・PD-ECGFの変化を伴う腎臓腎明細胞癌の症例では、PD-ECGFの変化を伴わない症例よりも全生存が悪い(図13);
・PD-ECGFの変化を伴う腎臓腎明細胞癌の症例では、PD-ECGFの変化を伴わない症例よりも無病生存が悪い(図14);
・PD-ECGFの変化を伴う腎臓腎明細胞癌の症例では、PD-ECGFの変化を伴わない症例よりも全生存が悪い(図15);
・PD-ECGFの変化を伴う腎臓腎乳頭細胞癌の症例では、PD-ECGFの変化を伴わない症例よりも無病生存が悪い(図16);
・PD-ECGFの変化を伴う肺腺癌の症例では、PD-ECGFの変化を伴わない症例よりも全生存が悪い(図17);
・PD-ECGFの変化を伴う肺腺癌の症例では、PD-ECGFの変化を伴わない症例よりも無病生存が悪い(図18);
・PD-ECGFの変化を伴う前立腺腺癌の症例では、PD-ECGFの変化を伴わない症例よりも無病生存が悪い(図19);
・PD-ECGFの変化を伴う精巣胚細胞癌の症例では、PD-ECGFの変化を伴わない症例よりも全生存が悪い(図20);
・PD-ECGFの変化を伴う胸腺腫の症例では、PD-ECGFの変化を伴わない症例よりも全生存が悪い(図21);
・PD-ECGFの変化を伴う胸腺腫の症例では、PD-ECGFの変化を伴わない症例よりも無病生存が悪い(図22);および
・PD-ECGFの変化を伴う甲状腺乳頭癌の症例では、PD-ECGFの変化を伴わない症例よりも全生存が悪い(図23)。
Claims (6)
- 対象における腎細胞癌(RCC)または結腸直腸癌の進行を予測するための方法であって、
(i)前記対象に由来する、血液サンプル、血清サンプルおよび血漿サンプルからなる群より選択される生体液サンプル中のPD-ECGFタンパク質のレベルを決定することと、
(ii)(i)で得られたレベルを基準値と比較することと、
を含み、
前記対象に由来する前記生体液サンプル中のPD-ECGFタンパク質のレベルが基準値と比較して増加している場合には、前記腎細胞癌(RCC)または結腸直腸癌が進行していることを示すものとし、
前記対象に由来する前記生体液サンプル中のPD-ECGFタンパク質のレベルが基準値と比較して減少している場合には、前記腎細胞癌(RCC)または結腸直腸癌が進行していないことを示すものとする、
方法。 - 前記生体液サンプルが、血漿サンプルである、請求項1に記載の方法。
- 前記腎細胞癌(RCC)または結腸直腸癌が、原発性腫瘍または転移癌である、請求項1または2に記載の方法。
- 前記基準値が、健康な対象に由来する、血液サンプル、血清サンプルおよび血漿サンプルからなる群より選択される生体液サンプルまたは腎細胞癌(RCC)または結腸直腸癌に罹患していない対象に由来する、血液サンプル、血清サンプルおよび血漿サンプルからなる群より選択される生体液サンプルにおいて決定される、請求項1~3のいずれかに記載の方法。
- PD-ECGFタンパク質のレベルが、ELISAまたはウエスタンブロットによって決定される、請求項1~4のいずれか一項に記載の方法。
- 対象における腎細胞癌(RCC)または結腸直腸癌の進行の予測における、前記対象に由来する、血液サンプル、血清サンプルおよび血漿サンプルからなる群より選択される生体液サンプル中のPD-ECGFタンパク質の使用。
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US11802874B2 (en) | 2023-10-31 |
ES2896056T3 (es) | 2022-02-23 |
EP3268744A1 (en) | 2018-01-17 |
KR102513020B1 (ko) | 2023-03-21 |
AU2016231086B8 (en) | 2022-02-03 |
HK1250582A1 (zh) | 2019-01-04 |
CN107667292A (zh) | 2018-02-06 |
CA2978653A1 (en) | 2016-09-15 |
AU2016231086A8 (en) | 2022-02-03 |
PL3268744T3 (pl) | 2021-12-27 |
AU2016231086B2 (en) | 2021-08-12 |
EP3067698A1 (en) | 2016-09-14 |
JP2018512585A (ja) | 2018-05-17 |
EP3268744B1 (en) | 2021-08-11 |
US20240069029A1 (en) | 2024-02-29 |
AU2016231086A1 (en) | 2017-09-28 |
JP2020201278A (ja) | 2020-12-17 |
KR20170123638A (ko) | 2017-11-08 |
WO2016142471A1 (en) | 2016-09-15 |
JP2022153482A (ja) | 2022-10-12 |
CN107667292B (zh) | 2020-06-19 |
US20180052164A1 (en) | 2018-02-22 |
MX2017011467A (es) | 2018-01-23 |
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